1. Field of the Invention
The present invention relates to rapid acting hypnotic agents formulations, especially zolpidem, having a modified release and to various pharmaceutical forms and uses thereof.
2. Description of the Related Arts
Various rapid acting hypnotics are known for inducing or maintaining sleep. Zolpidem, an imidazopyridine having IUPAC chemical nomenclature N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-s]pyridine-3-acetamide and represented by the following formula 
is one such hypnotic agent. The zolpidem free base was disclosed generically in EP 50563 of Synthelabo. Zolpidem tartrate was subsequently disclosed in EP 251859 (U.S. Pat. No. 4,794,185). More recently, zolpidem has been suggested as useful in treating Parkinson""s disease, parkinsonian symptoms, obsessive-compulsive disorder and certain forms of dementia in U.S. Pat. No. 5,891,891, the entire contents of which are incorporated herein by reference.
Zolpidem has been marketed as an immediate release tablet for oral application under the trade marks AMBIEN(copyright) and STILNOX(copyright). In these commercial pharmaceutical dosage forms, zolpidem is present as a salt with L(+)tartaric acid wherein the molar ratio of zolpidem to tartaric acid is 2:1. This salt is conventionally called zolpidem hemitartrate but a more correct denomination thereof, which will be used hereinafter, is zolpidem tartrate. Commercially available zolpidem tablets are conventional film coated tablets for immediate release of the active substance after ingestion and they contain 5 or 10 mg of zolpidem tartrate. The inactive ingredients are: lactose, microcrystalline cellulose, sodium starch glycolate, hydroxypropylmethylcellulose and magnesium stearate. The film coating layer consists of hydroxypropylmethylcellulose, polyethylene glycol and colorants.
A dissolution profile (i.e., the time dependence of the zolpidem concentration in aqueous phase after the final form is placed into a standardized aqueous environment) of the commercially available tablets is shown in FIG. 1. It is apparent that the dissolution curve is characterized by quick and rapid release of the entire amount of zolpidem from the tablet. This is consistent with the presence of a disintegrating agent in the tablet, namely sodium starch glycolate. Thus, the tablet is constituted in such a way that zolpidem release is not controlled by diffusion from the tablet matrix but by dispersion; the tablet disintegrates quite rapidly in the stomach and liberates almost immediately the whole bolus of zolpidem. Consequently, the ingestion of the tablet provides initially a considerably high serum concentration of zolpidem which is then metabolized. While zolpidem is a rapidly acting hypnotic, it is also a rapidly eliminated hypnotic agent. As a result, in therapy zolpidem starts acting within 15-30 minutes after ingestion of the tablet or even earlier and its action lasts for approximately 4-6 hours.
In certain situations this onset and duration of zolpidem action is undesirable. For example, quick dissolution of whole bolus of zolpidem from the commercial tablet may cause problems in zolpidem-sensitive patients; i.e., patients whose effective sleep-inducing plasma concentration of zolpidem is either lower than the average or is reached more quickly than the average patient. As a consequence, the onset of therapeutic action of zolpidem tablets may be too quick for zolpidem sensitive persons and this could be inconvenient, e.g., such patients may not have had enough time to prepare for and lie down before falling asleep.
Zolpidem is most effective when present in plasma within a certain concentration range. Above this range, there may be a danger that deleterious side effects may become manifest and even when there is not the danger, excess drug in the blood plasma may simply be wasted. Thus, an initial blood plasma concentration that exceeds the minimum effective concentration needed for inducing sleep may not manifest a proportionate therapeutic response and, on the other hand, the excess zolpidem cannot be used later as it is already metabolized or eliminated and thus wasted. As a result, the duration of action of the available zolpidem tablets is sometimes insufficiently short and thus does not accommodate a longer, uninterrupted and deep sleep.
Mutatis mutandis, this statement is valid also for similar hypnotic agents, such as zopiclon or zaleplon, used in immediate release oral dosage forms. Zopiclon is a compound of formula (2) and has been disclosed in U.S. Pat. No. 3,862,140, while zaleplon is a compound of formula (3) and has been disclosed in U.S. Pat. No. 4,626,538. 
Both compounds are used in pharmaceutical practice in rapid release oral compositions comprising, as the active ingredient, the respective compound in the form of its free base.
It is thus desirable to develop a pharmaceutical formulation for oral application of rapid acting hypnotic agent such as zolpidem that exhibits a fast but also a prolonged action at the same time. Delayed release and sustained release compositions and dosage forms, namely those in which a specific agent or device is present to act as a means for controlling the release rate of an active substance, are well known in the prior art. However, such conventional delayed/sustained release formulations are generally contrary to the purpose of a rapid acting hypnotic. The patient taking zolpidem desires the onset of the sleeping effect to be rapid. But a conventional sustained release formulation would delay the onset of sleep. Accordingly, the use of traditional release modifying agents such as acrylate polymers, would be expected to be inconsistent with the administration of a simple, rapid acting hypnotic dosage form.
Also, pharmaceutical compositions with proper modification of release rate are desirable when use of the rapidly acting hypnotic agent is for purposes other than for treatment of sleep disorders. For example, use of zolpidem in the above mentioned U.S. Pat. No. 5,891,891 for treating parkinsonian symptoms, should preferably provide a moderated onset and prolonged duration of the action, instead of an immediate release bolus.
As a result of thorough investigation of the matter, it has been found that rapid acting hypnotic agents, e.g., zolpidem, zopiclon, zaleplon, etc., can be formulated into a convenient pharmaceutical composition, especially into pellets, that exhibit a modified release profile which can effectively address the above disadvantages of the commercially available immediate release dosage forms.
Thus, a first aspect of the invention relates to a pharmaceutical pellet comprising a substantially homogenous mixture of a rapidly acting hypnotic agent or a pharmaceutically acceptable salt thereof and a pellet forming carrier, wherein said pellet exhibits a dissolution profile under US Pharmacopoeia XXIII, Dissolution method I, in a basket apparatus at temperature 37xc2x0 C., in 0.01N HCl medium and at 100 r.p.m., that includes 60% of the hypnotic agent being released from the pellet not earlier than 5 minutes from the start of the test. Preferably, the dissolution profile includes essentially 100% of the hypnotic agent being released from the pellet not earlier than 60 minutes from the start of the dissolution test. The rapid acting hypnotic agent is typically zolpidem, zopiclon, or zaleplon, preferably zolpidem free base or zolpidem hydrogen tartrate.
A second aspect of the invention relates to a pharmaceutical unit dosage form, comprising an effective amount of the above described pellets. The dosage form is preferably a capsule, but tablets, sachets, etc., are also included.
A third aspect of the invention relates to a method of using the pellets, which comprises inducing or maintaining sleep by administering an effective hypnotic amount of the above-described pellets to a mammal, preferably a human.
A fourth aspect of the present invention relates to a new and convenient method of making pharmaceutically acceptable spherical pellets. The pellets can be made with any active ingredient, including rapidly acting hypnotic agents and is thus also suitable for making the pellets of the above-described first aspect of the invention, but is not limited thereto. A process for making pharmaceutically acceptable spherical pellets, which comprises (1) combining a solvent, a pharmaceutically active agent and/or its pharmaceutically acceptable salt, and at least one pellet forming carrier to form a wet mixture, wherein the solvent is not combined by spraying; (2) stirring, chopping, or both, the wet mixture to form monolithic, spherical wet pellets; and (3) drying the wet pellets to form the intended pharmaceutically acceptable pellets.
Preferred embodiments of the present invention provide a composition that moderates the rapid release occurring in the commercial tablets to such extent that the possible initial over concentration of active agent in the body fluids is minimized and that the hypnotic action is reasonably delayed to overcome a shortage of sleep. Surprisingly it has been discovered that an oral composition based on a pellet is suitable for obtaining the desired modified release of the hypnotic agent.